cancer center stanford university gynecologic cancer treatment asco 2006 update: gynecologic cancers...

Cancer CenterCancer CenterStanford UniversityStanford University

Gynecologic Cancer Treatment

ASCO 2006 Update:ASCO 2006 Update:

Gynecologic CancersGynecologic Cancers

Amreen Husain, M.D.Amreen Husain, M.D.Assistant Professor Assistant Professor

Division of Gynecologic OncologyDivision of Gynecologic Oncology

Stanford University School of MedicineStanford University School of Medicine



OverviewOverview

• Ovarian cancerOvarian cancer• Benefit of adding a third drug?Benefit of adding a third drug?

• Intraperitoneal vs. intravenous?Intraperitoneal vs. intravenous?

• Benefit of Prolonged “maintenance” therapyBenefit of Prolonged “maintenance” therapy

• Use of Bevacizumab in ovarian cancerUse of Bevacizumab in ovarian cancer

• Endometrial cancerEndometrial cancer• Adjuvant therapy – radiation vs. chemotherapy? Adjuvant therapy – radiation vs. chemotherapy?

• laparoscopy vs. laparotomy?laparoscopy vs. laparotomy?



Ovarian CancerOvarian Cancer

Benefit of adding a third cytotoxic agent?Benefit of adding a third cytotoxic agent?



GOG0182-ICON5:

Phase III Randomized Trial of Paclitaxel and Carboplatin vs Combinations with Gemcitabine, PEG-Lipososomal

Doxorubicin, or Topotecan in Patients with Advanced-Stage Epithelial Ovarian or Primary Peritoneal Carcinoma

GOG, MRC, SWOG, ANZGOG,GOG, MRC, SWOG, ANZGOG,M Negri, and NCI-CTSUM Negri, and NCI-CTSU

Bookman, ASCO 2006



GOG0182-ICON5: SchemaGOG0182-ICON5: SchemaR

A N

D O

M I

Z E

R A

N D

O M

I Z

E

x8Carboplatin AUC 5 (d1)Paclitaxel 175 mg/m2 (d1)Doxil 30 mg/m2 (d1, every other cycle)

III

x8Carboplatin AUC 6 (d1)Paclitaxel 175 mg/m2 (d1)

I

Carboplatin AUC 6 (d1)Carboplatin AUC 6 (d1)Paclitaxel 175 mg/m 175 mg/m22 (d1) (d1)

x4

x4Carboplatin AUC 6 (d8)Gemcitabine 1 g/m2 (d1,8)

V

x4Carboplatin AUC 5 (d3)Topotecan 1.25 mg/m2 (d1-3)

IV

x8

Carboplatin AUC 5 (d1)Paclitaxel 175 mg/m2 (d1)Gemcitabine 800 mg/m2 (d1,8)

II

Bookman, ASCO 2006



GOG0182-ICON5: CharacteristicsGOG0182-ICON5: Characteristics

ARM:ARM: C+PC+P(n = 864)(n = 864)

C+P+GC+P+G(n = 864)(n = 864)

C+P+DC+P+D(n = 862)(n = 862)

CTCTCPCP(n = 861)(n = 861)

CGCGCPCP(n = 861)(n = 861)

Age (Median)Age (Median) 57.7 y57.7 y 59.1 y59.1 y 59.5 y59.5 y 58.5 y58.5 y 59.3 y59.3 y

FIGO Stg IVFIGO Stg IV11º Peritonealº Peritoneal

16.2%16.2%13.3%13.3%

13.3%13.3%13.0%13.0%

13.8%13.8%14.5%14.5%

13.7%13.7%12.7%12.7%

16.3%16.3%12.8%12.8%

0%

25%

50%

75%

100%

Other / PendingMucinous Clear Cell Endometrioid Papillary Serous



GOG0182-ICON5: StratificationGOG0182-ICON5: Stratification

ARM:ARM: C+PC+P(n = 864)(n = 864)

C+P+GC+P+G(n = 864)(n = 864)

C+P+DC+P+D(n = 862)(n = 862)

CTCTCPCP(n = 861)(n = 861)

CGCGCPCP(n = 861)(n = 861)

MeasurableMeasurableInterval SurgeryInterval Surgery

21.6%21.6% 7.7%7.7%

22.6%22.6% 8.2%8.2%

22.7%22.7% 7.7%7.7%

23.3%23.3% 7.1%7.1%

24.2%24.2% 7.8%7.8%

0%

25%

50%

75%

100%

Microscopic

<=1 cm Optimal

> 1 cm Subopt

Bookman, ASCO 2006



GOG0182-ICON5: Heme ToxicityGOG0182-ICON5: Heme Toxicity

0%

10%

20%

30%

40%

50%

60%

70%

80%

ANC*(Grade:4+)

Plts*(Grade:3+)

Hgb*(Grade:3+)

Fever/Inf*(Grade:3+)

ControlGem TripletPLD TripletTopo DoubletGem Doublet

* p < 0.001 global test of null hypothesisBookman, ASCO 2006



GOG0182-ICON5: Non-Heme ToxicityGOG0182-ICON5: Non-Heme Toxicity

0%

5%

10%

15%

20%

25%

30%

Neuropathy*(Grade:2+)

Pulmonary(Grade:2+)

Hepatic*(Grade:2+)

ControlGem TripletPLD TripletTopo DoubletGem Doublet

* p < 0.001 global test of null hypothesis Bookman, ASCO 2006



GOG0182-ICON5: Overall SurvivalGOG0182-ICON5: Overall Survival

Bookman, ASCO 2006



GOG0182-ICON5: GOG0182-ICON5: Progression-Free SurvivalProgression-Free Survival

Median PFS and HR (95% CI)Median PFS and HR (95% CI)

16.1 1.00016.1 1.00016.4 0.990 (0.884-1.107)16.4 0.990 (0.884-1.107)16.4 0.998 (0.891-1.117)16.4 0.998 (0.891-1.117)15.3 1.094 (0.979-1.224)15.3 1.094 (0.979-1.224)15.4 1.052 (0.940-1.176)15.4 1.052 (0.940-1.176)

Bookman, ASCO 2006



GOG0182-ICON5: Overall SurvivalGOG0182-ICON5: Overall Survival

Median OS and HR (95% CI)Median OS and HR (95% CI)

40.0 1.00040.0 1.00040.4 0.978 (0.838-1.141)40.4 0.978 (0.838-1.141)42.8 0.972 (0.832-1.136)42.8 0.972 (0.832-1.136)39.1 1.068 (0.918-1.244)39.1 1.068 (0.918-1.244)40.2 1.035 (0.888-1.206)40.2 1.035 (0.888-1.206)

Bookman, ASCO 2006



GOG0182-ICON5: ConclusionsGOG0182-ICON5: Conclusions

• The addition of a third cytotoxic agent was associated with

increased, but manageable, hematologic toxicity

• A third cytotoxic agent was not associated with improved clinical

outcomes, including progression-free and overall survival

• After more than 25 years, carboplatin remains the dominant agent

for treatment of advanced ovarian cancer, with an impact on

evaluation of new agents and potential non-platinum alternatives

Bookman, ASCO 2006



Ovarian CancerOvarian Cancer

Intraperitoneal vs. Intravenous chemotherapy?Intraperitoneal vs. Intravenous chemotherapy?



Intraperitoneal chemotherapy Intraperitoneal chemotherapy

PFSPFS IVIV 18.3 Months18.3 Months

IPIP 24 Months24 Months

OSOS IVIV 49.7 Months49.7 Months

IPIP 65.6 Months65.6 Months

GOG 172• N = 416, Stage III, Optimal (<1cm) • Randomized trial

• Group 1Paclitaxel 135 mg/m2/24hCisplatin 75 mg/m2 q 21 days x 6

• Group 2Paclitaxel 135 mg/m2/24hCisplatin 100 mg/m2 IP D2Paclitaxel 60 mg/m2 IP D8q 21 days x 6

• Quality of life:• Greater short term decline• No difference after 12 months

Armstrong et al, NEJM 2006



Figure 2

By Treatment GroupP

ropo

rtio

n S

urvi

ving

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months on Study0 12 24 36 48 60

l IV

IP



Wensel ASCO 2006

Patient-Reported FACT-O Scores

70

80

90

100

110

120

130

140

Pre-Randomization Pre-4th Cycle 3~6 Weeks Post 6thCycle

12 Months Post 6thCycle

IV IP



Baseline Quality of Life and Tolerance for Intraperitoneal Chemotherapy for Baseline Quality of Life and Tolerance for Intraperitoneal Chemotherapy for Advanced Epithelial Ovarian Cancer: A GOG StudyAdvanced Epithelial Ovarian Cancer: A GOG Study

• To determine if patient-reported baseline QOL scores are associated with number of IP cycles To determine if patient-reported baseline QOL scores are associated with number of IP cycles completed in the GOG 172completed in the GOG 172

• Results –Results –

higher FACT-O scores significantly more likelyhigher FACT-O scores significantly more likely• to complete more IP cycles (OR: 1.27 for every 10 points; 95% CI: 1.11 ~ 1.46; p<0.001), to complete more IP cycles (OR: 1.27 for every 10 points; 95% CI: 1.11 ~ 1.46; p<0.001), • to tolerate 6 cycles of IP therapy (OR: 1.31 for every 10 points; 95% CI: 1.11 ~ 1.56; to tolerate 6 cycles of IP therapy (OR: 1.31 for every 10 points; 95% CI: 1.11 ~ 1.56;

p=0.002)p=0.002)• Conclusions – Conclusions –

– Baseline QOL associated with tolerance to IP chemotherapy and may be useful in Baseline QOL associated with tolerance to IP chemotherapy and may be useful in identifying those at risk for serious toxicitiesidentifying those at risk for serious toxicities

Wensel ASCO 2006



Wensel ASCO 2006



• Question of abstracts 5004Question of abstracts 5004(Markman et al.)(Markman et al.)

Will 12 months of paclitaxel prolong Will 12 months of paclitaxel prolong survival in patients with clinical survival in patients with clinical complete remission after primary complete remission after primary treatment?treatment?



Progression-Free Survival

0%

20%

40%

60%

80%

100%

0 24 48 72 96

Months After Registration

Paclitaxel 12 coursesPaclitaxel 3 courses

At Risk150146

Failed102115

Medianin Months

2214

P=0.01P=0.01



Overall Survival

0%

20%

40%

60%

80%

100%

0 24 48 72 96Months After Registration

Paclitaxel 12 coursesPaclitaxel 3 courses

At Risk150146

Deaths6680

Medianin Months

5346

P=0.27P=0.27



Increased PFS butIncreased PFS but::

• More time on first line treatment and toxicityMore time on first line treatment and toxicity• Equal treatment free interval= equal Equal treatment free interval= equal

symptoms and toxicity-free survivalsymptoms and toxicity-free survival• Potential for decreased tolerance to Potential for decreased tolerance to

subsequent treatment (g 2-3 neuropathy)subsequent treatment (g 2-3 neuropathy)• No increased in survivalNo increased in survival



Abstract 5004: Clinical implicationAbstract 5004: Clinical implication

1 12treatmenttreatment 22Treatment and PFS = 10 mos

PFS=22 mosPFS=22 mos

Treatment and PFS = 11 mos

1 14

3

PFS=14 mosPFS=14 mos



BevacizumabBevacizumab

15 mg/kg IV q 3 wks15 mg/kg IV q 3 wks

Cannistra, et al, ASCO 2006Cannistra, et al, ASCO 2006

• 44 patients

• recurrent / persistent ovarian or primary peritoneal ca

• Progression within <6 mos

• No more than 3 prior therapies

PPhhaassee IIII

Recurrent ovarian - Bevacizumab – multicenter phase IIRecurrent ovarian - Bevacizumab – multicenter phase II

• Response:Overall = 15.9%

– CR = 0

– PR = 7

– SD = 11

• Median Duration: 4.2 mos

• Toxicity (Grade 3):– 5 htn, 3 MI, 1 CVA, 1 pulm

htn, 1 bldg, 5 GI perforation



Comparison with other trials

16%27.4%

Platinum refractory resistant,

up to 3 regimens

Single agent BV 15 mg/kg

q 3 wk

Current Study(N = 44)

Prior Treatment Setting

Efficacy Results ORR 6-mo PFS

Study Treatment

42% DDP sensitiveup to 2 prior

regimens

42% DDP sensitive

up to 2 prior regimens

28%57%

18%39%

BV 10 mg/kg q 2 wks + low dose oral

cytoxan

Single agent BV 15 mg/kg q

3 wk

NCI 5789**(N = 29)

GOG 170-D*(N = 63)



GI PerforationsGI Perforations

• Five GI perforations observed in this trialFive GI perforations observed in this trial– Four occurred within 9 weeks of initiating therapyFour occurred within 9 weeks of initiating therapy– Perforation confirmed surgically in 4 cases; 5th developed Perforation confirmed surgically in 4 cases; 5th developed

large pelvic abscesslarge pelvic abscess– One fatality out of 5 GIP cases despite surgical intervention One fatality out of 5 GIP cases despite surgical intervention

• IND Action letter (NIH) - Oct 4, 2005 IND Action letter (NIH) - Oct 4, 2005 – Alerted investigators of risk of GI perforationsAlerted investigators of risk of GI perforations– CTEP database: 144 pts with 1 perforation and 3 fistulas (2.8%)CTEP database: 144 pts with 1 perforation and 3 fistulas (2.8%)– Total 4+5/144+44= 4.8% risk of perforationTotal 4+5/144+44= 4.8% risk of perforation



Bevacizumab: Clinical implications

• Activity confirmed in relapsed ovarian cancer

• Should be avoided in heavily pretreated patients with:

– Extensive bowel involvement

– Bowel obstruction

– Bowel wall thickening



Endometrial cancerEndometrial cancer

– Adjuvant therapy – radiation vs. chemotherapy? Adjuvant therapy – radiation vs. chemotherapy?

– laparoscopy vs. open surgery?laparoscopy vs. open surgery?



Abdomino (Abdomino (3000 cGy)PelvicRadiation (PelvicRadiation (4980 cGy)

Vs.Vs.

Cisplatin 20 mg/m2/d x 4 d

Ifosfamide 1.5 g/m2 x 4 dMesna 120 mg/m2 IV bolus over 15 minutes then 1.5 g/m2/d IV infusion over 24 hrs.

Repeated q 3 weeks x 3 cycles

• 206 eligible with carcinosarcoma of uterus

• Stage I-IV• TAH/BSO• Debulking to <1cm• washings, PA node

sampling and omental biopsy optional

• 1993-2005

RRAANNDDOOMMIIZZEE

• Endpoints –Endpoints –

• PFS and OS PFS and OS

• ToxicityToxicity

GOG 150 - Uterine Carcinosarcoma GOG 150 - Uterine Carcinosarcoma

Wolfson, ASCO 2006Stage I (31%), II (13%), III (45%), IV (11%)



By Randomized Treatment

Pro

port

ion

Sur

vivi

ng

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months on Study0 12 24 36 48 60 72 84 96

Treatment Group Alive Died Total Whole Abdm RT 39 66 105

Alive Died Total

Cispt+Ifos 48 53 101

Estimate 5 year survival - WAI - 34%CIM - 47%

• CIM improves PFS CIM improves PFS and OS compared and OS compared whole abdomino whole abdomino pelvic irradiationpelvic irradiation

• With increased With increased vaginal, decreased vaginal, decreased distant recurrencedistant recurrence

• More acute anemia More acute anemia & neuropathy, less & neuropathy, less chronic GI toxicitychronic GI toxicity



• Adjuvant chemotherapy is more effective with less long term toxicity Adjuvant chemotherapy is more effective with less long term toxicity

than radiotherapy in reducing recurrence and prolonging the survival than radiotherapy in reducing recurrence and prolonging the survival

of patient with optimally debulked uterine CSof patient with optimally debulked uterine CS

• Future therapeutic trials for this patient population should consider Future therapeutic trials for this patient population should consider

at least adjunctive vaginal brachytherapy and 3 cycles of CIM as a at least adjunctive vaginal brachytherapy and 3 cycles of CIM as a

“control arm”“control arm”

GOG 150 - Conclusions

Wolfson, ASCO 2006



Early endometrial ca – laparoscopy GOG LAP2Early endometrial ca – laparoscopy GOG LAP2

Laparoscopy Laparoscopy (n=1696)(n=1696)

Laparotomy Laparotomy

(n=920)(n=920)

RRAANNDDOOMMIIZZEE

•2616 patients2616 patients

•Clinical stage I/IIAClinical stage I/IIA

•2:1 randomization2:1 randomization

•Lymph node fromLymph node from

R & L pelvic/PAR & L pelvic/PA

•1996-20051996-2005

Walker, SGO 2006Walker, SGO 2006

Results – Results – • 23% conversion rate for poor 23% conversion rate for poor

exposure, bleedingexposure, bleeding• Length of stay shorter with Length of stay shorter with

laparoscopy, 2 vs 4 dayslaparoscopy, 2 vs 4 days• OR time longer with OR time longer with

laparoscopy, 3.3h vs. 2.2hlaparoscopy, 3.3h vs. 2.2h• Fewer G2 or higher morbidityFewer G2 or higher morbidity• Acceptable alternativeAcceptable alternative



Early endometrial ca – laparoscopy GOG LAP2 - QOLEarly endometrial ca – laparoscopy GOG LAP2 - QOL

Laparoscopy Laparoscopy

(n=524)(n=524)

Laparotomy Laparotomy

(n=258)(n=258)

RRAANNDDOOMMIIZZEE

•782 patients782 patients

•Clinical stage I/IIAClinical stage I/IIA

•FACT-G – physical, FACT-G – physical, emotional, social well emotional, social well being before, 1,3,6 being before, 1,3,6 wks and 6 mos after wks and 6 mos after surgerysurgery

Kornblith et al, SGO 2006Kornblith et al, SGO 2006

Results – Results – •QOL significantly higher with QOL significantly higher with

laparoscopy at 1 wk, 3 wks, and 6 laparoscopy at 1 wk, 3 wks, and 6

wks after adjusting for baseline wks after adjusting for baseline

scoresscores• No difference at 6 monthsNo difference at 6 months• OR time longer with OR time longer with

laparoscopy, 3.3h vs. 2.2hlaparoscopy, 3.3h vs. 2.2h• no difference in acute peri-no difference in acute peri-

operative morbidity or wound operative morbidity or wound

complicationscomplications



Pre

dict

ed P

roba

bilit

y of

Suc

cess

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

BMI

0 5 10 15 20 25 30 35 40 45 50 55 60

74% success

Predicted Probability of Successful Laparoscopy by BMI - Updated

% SUCCESSFULLAPAROSCOPY

BMI



Median Number of Nodes at Each Site

0

2

4

6

8

10

12

Left PA Right PA Left Pelvic RightPelvic

Lymph Node Location

Nu

mb

er o

f N

od

es

Open Arm

Scope Arm

Successful Scope

Convert to Open



Pelvic Cytology: Randomization Arm

0.00%

1.00%

2.00%

3.00%

4.00%

5.00%

6.00%

7.00%

positive susp missing

Cytology Result

Per

cen

t

open

scope

p= 0.010



• Laparoscopy is an acceptable alternative to laparotomy for uterine cancer treatment and staging.

– Surgeons were encouraged to convert to laparotomy when they encountered metastatic disease.

– Conversion to laparotomy is advised when incomplete staging results would yield inadequate information for treatment planning.

– Previously reported QOL improvement and decreased hospital stay, fewer grade > 2 complications makes laparascopic staging desirable from a patient perspective.

– Survival results are pending.



ReviewReview

• Ovarian cancerOvarian cancer– 33rdrd agent does not improve outcome agent does not improve outcome– Intraperitoneal therapy for selected patientsIntraperitoneal therapy for selected patients– Prolonged therapy does not improve outcome.Prolonged therapy does not improve outcome.

• Endometrial cancer Endometrial cancer – Laparoscopy is an alternative for selected patientsLaparoscopy is an alternative for selected patients– Adjuvant therapy –chemotherapy better than radiationAdjuvant therapy –chemotherapy better than radiation

cancer center stanford university gynecologic cancer treatment asco 2006 update: gynecologic cancers...

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